Cooh Hc

Figure 1.8 (a) Effect of anionic and cationic surfactants on the habit of adipic acid crystals. (b) A diagrammatic (not to scale) representation of the arrangement of molecules at the crystal surface.

(001) face (anionic)

(110) face (hydrophobic)

(010) face (hydrophobic)

Figure 1.8 (a) Effect of anionic and cationic surfactants on the habit of adipic acid crystals. (b) A diagrammatic (not to scale) representation of the arrangement of molecules at the crystal surface.

Surfactants in the solvent medium used for crystal growth (or, for example, in stabilisation or wetting of suspensions) can alter crystal form by adsorbing onto growing faces during crystal growth. This is best illustrated by the effect of anionic and cationic surfactants on the habit of adipic acid crystals.3 X-ray analysis showed that the linear six-carbon dicarboxylic acid molecules were aligned end-to-end in a parallel array in the crystal with their long axis parallel to the (010) faces, so that the (001) face is made up entirely of -COOH groups while the (010) and (110) faces contain both -COOH and hydrocarbon (HC) portions of the molecule (Fig. 1.8). The cationic surfactant trimethyldodecylam-monium chloride is twice as effective in hindering the growth of the (001) face as that of the (110) and (010) faces. In high concentrations it causes the formation of very thin plates or flakes. Conversely, the anionic surfactant sodium dodecylbenzene sulfonate at 55 ppm (parts per million) is three times as effective in reducing the growth rates of the (110) and (010) faces as of the (001) face. Higher levels of sodium dodecylbenzene sulfonate cause extreme habit modification, producing not hexagonal plates but long, thin rods or needles. The crystallographic faces whose growth rates are depressed most are those upon which surfactant adsorption is the greatest. Cationic additives adsorb on the face composed of carboxylic groups (001), and anionic additives on the (110) and (200) faces, which are hydrophobic. A coulombic interaction of the cationic head groups and the -COO- groups on the (001) faces has been suggested. The adsorption of the anionic surfactant, repelled from the anionic (001) faces, takes place amphipathically on the hydrophilic (110) faces and (100) faces (Fig. 1.8).

1.3 Polymorphism4

As we have seen, compounds can crystallise out of solution in a variety of different habits depending on the conditions of crystallisation.

These crystal habits usually have the same internal structure and so have the same X-ray diffraction patterns. A more fundamental difference in properties may be found when the compounds crystallise as different polymorphs. When polymorphism occurs, the molecules arrange themselves in two or more different ways in the crystal; either they may be packed differently in the crystal lattice or there may be differences in the orientation or conformation of the molecules at the lattice sites. These variations cause differences in the X-ray diffraction patterns of the polymorphs and this technique is one of the main methods of detecting the existence of polymorphs. The polymorphs have different physical and chemical properties; for example, they may have different melting points and solubilities and they also usually exist in different habits.

We will consider two drugs that exhibit this phenomenon. Spironolactone (I), which is a diuretic steroidal aldosterone agonist, crystallises as two polymorphic forms and also as four solvated crystalline forms depending on the solvents and methods used for crystallisation. 5 We will consider the occurrence of solvated forms in section 1.4; at the moment we will concentrate on the two polymorphs only. Form 1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to 0°C. Form 2 is produced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to spontaneously evaporate over a period of several weeks. In both poly-morphs the steroid nuclei (A, B, C and D rings)